Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin a), and neurokinin B (also known as neuromedin K and neurokinin .beta.). See, J. E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches. see. e.g., S. L. Shepheard, et al., British Journal of Pharmacology 108:11-20 (1993); S. M. Moussaoui, et al., European Journal of Pharmacology, 238:421-424 (1993); and W. S. Lee, et al., British Journal of Pharmacology, 112:920-924 (1994).
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in U.S. Pat. No. 5,328,927, issued Jul. 12, 1994; U.S. Pat. No. 5,360,820, issued Nov. 1, 1994; U.S. Pat. No. 5,344,830, issued Sep. 6, 1994; U.S. Pat. No. 5,331,089, issued Jul. 19, 1994; European Patent Publication 591,040 A1, published Apr. 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published Jan. 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published Mar. 3, 1994; and Patent Cooperation Treaty publication WO 93/011609, published Jan. 21, 1993.
Sleep apnea is a condition in which apnea coours during sleep without subjective symptom. It is more prevailing in male middle and old-aged persons in their forties and fifties. Approximately one per 100 persons is reported to suffer from this condition. In sleep apena there is repeated many times in sleep a sequence of 20-40 seconds apnea, about 10-20 seconds pneusis, and 20-40 seconds apnea. For example, during a 6.5 hour sleep, approximately 400 occurrences of apnea may occur.
As a result of sleep apnea there occur phenomena, such as daytime sleepiness, loss of energy or appetite, swelling in the lower part of the body, and shortness of breath. Increase in leukocyte number, development of polycythemia, and even cardiomegaly are associated with severe instances of sleep apnea. Sleep apnea is observed not only in adults of middle or advanced age, but also in infants, and may be an indirect cause of hypertension, cardiac insufficiency, and arrhythmia, possibly being a leading cause of sudden infant death syndrome.
Several thousand apparently healthy infants (children under the age of one year) die each year in the United States from Sudden Infant Death Syndrome (SIDS). Deaths from SIDS have been estimated at 7,000 to 10,000 per year. The occurrence of SIDS in a given family can be particularly devastating emotionally because, in general, there is no warning that the infant is at risk and the parent or care giver has no knowledge of any problem until he or she discovers an unconscious or deceased infant thought to be safely sleeping in its crib.
Therapies currently adopted for sleep apnea include bodyweight reduction, pressure application through the nose, surgical operation, and the use of a drug, such as acetazolamide. U.S. Pat. No. 5,422,374, issued Jun. 6, 1995, describes the use of ubidecarenone to treat sleep apnea. U.S. Pat. No. 5,356,934, issued Oct. 18, 1994, describes the use of serotonin agonists, most preferably (R)-fluoxetine, to treat sleep apnea. Both of these patents are herein incorporated by reference.
Because of the current dissatisfaction of the currently marketed treatments for sleep apnea within the affected population, there exists a need for a more efficacious and safe treatment.